Hi Suresh,
Endophenotype is a term most commonly used to describe a trait in a complex neuropsychiatric disorder. The term was adapted from John and Lewis, two scientists who used it to explain concepts in evolution and insect biology. While the term phenotype describes an external feature or a trait we can see, the term endophenotype depicts a trait that is microscopic and internal.

As you probably know, some mental disorders are associated with a combination of mutations in several genes. To make finding cures more difficult, epigenetic factors or the environment can also significantly influence the manifestation state of the disease. Therefore, endophenotypes can help to dissect the description of a disease into many measurable and comparable factors. The trait can be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological.

For example, in the study of schizophrenia, we can measure the degree of sensory motor gating deficits or prepulse inhibition (i.e., the ability to inhibit one’s reaction to startling stimuli). Bipolar disorder and attention deficit hyperactivity disorder (ADHD) are examples of additional mental disorders that benefit from using the endophenotype approach to dissect the components that underlie them.

In order for endophenotypes to be useful in describing a mental disorder, they must be linked to the disease and passed on from generation to generation. Even with this terminology, there is still much variation among different individuals with the same disease, making the study of these diseases a real challenge!

To learn more about endophenotypes, we encourage you to follow the links we’ve provided below. Happy reading!

Follow this link to an overview of endophenotypes:

http://ajp.psychiatryonline.org/cgi/content/full/160/4/636

To learn more about endophenotypes, follow these links:

http://onlinelibrary.wiley.com/doi/10.1111/j.1601-183X.2005.00186.x/full

http://bjp.rcpsych.org/cgi/content/full/178/5/395

http://archpsyc.ama-assn.org/cgi/content/full/61/10/974

http://schizophreniabulletin.oxfordjournals.org/content/33/1/21.full

http://www.annualreviews.org/doi/abs/10.1146/annurev.clinpsy.2.022305.095232?journalCode=clinpsy

As there are two sides to every story, here is a link to a commentary that examines the validity and the benefits of using the term endophenotype:

http://journals.cambridge.org/action/displayFulltext?type=6&fid=658036&jid=PSM&volumeId=37&issueId=02&aid=658028&bodyId=&membershipNumber=&societyETOCSession=&fulltextType=PI&fileId=S0033291706008750

Hello Rakeshb,
Yes, scientists often change their fields of study, and it is certainly possible to enter a doctoral program in Clinical Genetics after you complete your M.Sc. in Genetics and Plant Breeding. We recommend that you do some research to identify schools that best fit your academic needs. Then, you should research each school specifically to determine their international student admissions requirements and student resources. If you are interested in a particular aspect of clinical genetics, then it is important to research faculty interests to be sure that you will have a great faculty mentor. We hope you find a school that suits you, and good luck with your applications!

Check out the following links to begin researching schools:

http://www.arwu.org/index.jsp

http://chronicle.com/article/NRC-Rankings-Overview-/124733/

Welcome back Shikha,
As you likely know by now, RNA interference (RNAi) is a fascinating cellular phenomenon. You’ll certainly have a lot to talk about during your presentation, and the members your audience will undoubtedly be on the edge of their seats! With a time limit of one hour, you’ll be able to provide a lot of great information. We recommend beginning with a discussion of how RNAi was discovered, followed by details about how it works and how it is being developed to combat diverse forms of human disease. We’d like to provide you with a brief introduction to these three topics to help get you started.

How was RNAi discovered? The underlying molecular details of this process were uncovered through the Nobel-prize-winning experiments of Andrew Fire and Craig Mello, who discovered that a certain gene (called a target gene) can be turned “off” in worms when they eat E. coli that express a double-stranded RNA (dsRNA) molecule complementary to the target gene. RNAi is now known to occur in insects, plants, fish, and mammals (including humans).

Now, let’s discuss how RNAi works. In a nutshell, RNAi refers to the process wherein a short double-stranded RNA — called a short inhibitory RNA (siRNA) — targets an mRNA for destruction in several steps. The multi-step RNAi pathway uses two different cellular enzyme complexes to: 1. cut up the targeting siRNA into shorter fragments and 2. inhibit the expression of the corresponding mRNA (by cleaving it or by interfering with its translation).

As a grand finale, your audience will certainly be interested to hear that major efforts are currently focused on the development of RNAi-based therapeutics for the treatment of diverse forms of human disease, including cancer, neurodegenerative disease, diabetes, and more. In terms of targeting a particular disease, the idea is that RNAi would facilitate the destruction of an mRNA coding for a protein that’s involved in a disease — so elimination of that protein may help treat the disease. In fact, RNAi-based therapies for targeting degenerative eye disease have shown promising results in recent years. Many believe that RNAi-based approaches will provide new therapeutic opportunities to target genes that have been resistant to traditional targeting approaches.

We’ve provided a series of links to helpful websites and scientific articles focused on these three important topics. We hope they are useful to you as you are putting your presentation about RNAi together. Best of luck to you!

To learn more about RNAi on Scitable, check out this article:

http://www.nature.com/scitable/topicpage/Small-Non-coding-RNA-and-Gene-Expression-1078

Here are some other resources about RNAi, including its discovery in worms and its therapeutic potential in humans:

http://nobelprize.org/nobel_prizes/medicine/laureates/2006/adv.html

http://www.wormbook.org/chapters/www_introreversegenetics/introreversegenetics.html#d0e46

The review articles below provide useful information about siRNA-based therapeutics for cancer and other diseases:

http://www.nature.com/cgt/journal/v13/n9/full/7700931a.html

http://www.jci.org/articles/view/34274

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978219/?tool=pubmed

http://www.nature.com/nchembio/journal/v2/n12/full/nchembio839.html

http://www.nature.com/mt/journal/v18/n3/full/mt2009306a.html

Here’s an interesting paper that discusses the challenges of delivering RNAi-based therapeutics:

http://www.nature.com/nrd/journal/v8/n7/full/nrd2940.html

Below, find links to helpful animations, a great movie, an interview with a leading RNAi researcher, and slideshows that demonstrate how RNAi is induced in a cell:

http://www.nature.com/scitable/content/RNAi-Animation-2647104

http://www.pbs.org/wgbh/nova/body/rnai.html

http://www.pbs.org/wgbh/nova/body/rnai-explained.html

http://www.pbs.org/wgbh/nova/body/hannon-rnai.html

http://www.hhmi.org/biointeractive/rna/rna_interference/01.html

Hello Sobia,
Geneticists often set up matings between different strains of model organisms (e.g., flies, worms, yeast, mice) when trying to determine inheritance patterns associated with a phenotype of interest. As you know, when we want to understand the inheritance patterns associated with a given phenotype or disorder in humans, we cannot simply set up matings between selected human beings. Rather, human geneticists analyze inheritance patterns in human families using pedigree charts to determine whether a given phenotype or disorder is autosomal, sex-linked, recessive, or dominant. We’ll begin with an overview of pedigree notation, followed by some examples of common inheritance patterns. In a nutshell, pedigrees are like family trees that provide information about family members, including their sex, traits (e.g., disease phenotypes), and relationships to each other.

Roman numerals positioned on the right- or left-hand side of the pedigree indicate the generation number. Squares are used to represent males, circles are used to represent females, and diamonds are used when the sex of an individual is not known. Open symbols are used to represent unaffected individuals, and filled-in symbols are used to indicate family members affected with the trait in question. A single horizontal line connecting male and female indicates a mating; a double horizontal line connecting a male and female indicates a mating between family members (also referred to as a consanguineous mating). A horizontal line above a group of family members indicates that they are children of the same set of parents; siblings are typically ordered from left to right according to their birth order. Carriers are indicated by the presence of a dot within the symbol, and deceased individuals are indicated by a diagonal slash through the symbol. With this information in hand, you can begin to interpret pedigrees and determine inheritance patterns.

Now, let’s consider some of the inheritance patterns that can be tracked using pedigrees. We’ll start with autosomal recessive disorders. Autosomal recessive disorders affect males and females equally. Individuals that manifest an autosomal recessive disorder must be homozygous for the disease-associated allele. Autosomal recessive disorders often occur among siblings of two unaffected parents who are both carriers. When both parents are carriers, they will have a 25% chance of having a child with the disorder and a 75% chance of having an unaffected child; their unaffected children will have a 66.7% chance of being carriers. If the autosomal recessive disorder is very rare, it is more likely to be the result of a consanguineous mating. Autosomal recessive disorders most often skip generations or occur sporadically.

In the case of autosomal dominant disorders, males and females will also be equally affected. Individuals that manifest an autosomal dominant disorder can be either heterozygous or homozygous for the disease-associated allele. If one parent is heterozygous for the disease-associated allele, his offspring will have a 50% chance of having the disorder. If one parent is homozygous for the disease-associated allele, all his offspring will have the disorder. Autosomal dominant disorders often occur in every generation.

Let’s move on to X-linked recessive disorders. Females with an X-linked recessive disorder must inherit the disease-associated allele from both parents. Males are hemizygous for the X chromosome (i.e., they have a single X chromosome, which always comes from their mother). Therefore, males with an X-linked recessive disorder always inherit the disease-associated allele from their mother. X-linked recessive disorders are much more common among men than women. If the female parent is a carrier (i.e., she is heterozygous), her sons will have a 50% chance of having the disorder and her daughters will have a 50% chance of being carriers. If the female parent has the disorder (i.e., she is homozygous), all her sons would have the disorder and all her daughters would be carriers. If the male parent has the X-linked disorder, he would pass on the disease-associated allele to all his daughters: all his daughters would be carriers, but none of his sons would carry the disease-associated allele.

Finally, let’s discuss how X-linked dominant disorders can be identified in pedigrees. Females with an X-linked dominant disorder can be either homozygous or heterozygous. If a female is homozygous for an X-linked dominant allele, all her sons and daughters will have the disorder. If a female is heterozygous for an X-linked dominant allele, her daughters and sons will have a 50% chance of having the disorder. If a male has the X-linked dominant disorder, all his daughters would have the disorder, but none of his sons would have the disorder.

To sum this up, autosomal recessive and autosomal dominant disorders affect males and females equally. However, whereas autosomal recessive disorders skip generations or occur sporadically, autosomal dominant disorders often occur in every generation. X-linked recessive disorders occur much more frequently in males than females. X-linked recessive disorders will be passed on from unaffected female carriers to half of their sons while all the daughters of affected males will be carriers. In contrast, X-linked dominant disorders will be passed on from affected females to their sons or daughters, from affected males to all their daughters but none of their sons.

We hope this introduction to pedigrees and their interpretation will help you with your genetics case studies. For more information about pedigrees and how they can be used to determine patterns of inheritance, check out the links below:

http://www.nature.com/scitable/topicpage/Gregor-Mendel-and-the-Principles-of-Inheritance-593

http://www.uvm.edu/~cgep/Education/Inheritance2.html

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hmg&part=A242

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hmg&part=A242&rendertype=figure&id=A246

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mga&part=A518